Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Am J Pathol. 2011 Oct;179(4):1719-32. doi: 10.1016/j.ajpath.2011.06.033. Epub 2011 Aug 11.
The transient receptor potential channel C6 (TRPC6) is a slit diaphragm-associated protein in podocytes involved in regulating glomerular filter function. Gain-of-function mutations in TRPC6 cause hereditary focal segmental glomerulosclerosis (FSGS), and several human acquired proteinuric diseases show increased glomerular TRPC6 expression. Angiotensin II (AngII) is a key contributor to glomerular disease and may regulate TRPC6 expression in nonrenal cells. We demonstrate that AngII regulates TRPC6 mRNA and protein levels in cultured podocytes and that AngII infusion enhances glomerular TRPC6 expression in vivo. In animal models for human FSGS (doxorubicin nephropathy) and increased renin-angiotensin system activity (Ren2 transgenic rats), glomerular TRPC6 expression was increased in an AngII-dependent manner. TRPC6 expression correlated with glomerular damage markers and glomerulosclerosis. We show that the regulation of TRPC6 expression by AngII and doxorubicin requires TRPC6-mediated Ca(2+) influx and the activation of the Ca(2+)-dependent protein phosphatase calcineurin and its substrate nuclear factor of activated T cells (NFAT). Accordingly, calcineurin inhibition by cyclosporine decreased TRPC6 expression and reduced proteinuria in doxorubicin nephropathy, whereas podocyte-specific inducible expression of a constitutively active NFAT mutant increased TRPC6 expression and induced severe proteinuria. Our findings demonstrate that the deleterious effects of AngII on podocytes and its pathogenic role in glomerular disease involve enhanced TRPC6 expression via a calcineurin/NFAT positive feedback signaling pathway.
瞬时受体电位通道 C6（TRPC6）是足细胞中裂孔隔膜相关蛋白，参与调节肾小球滤过功能。TRPC6 的功能获得性突变导致遗传性局灶节段性肾小球硬化（FSGS），几种人类获得性蛋白尿疾病显示肾小球 TRPC6 表达增加。血管紧张素 II（AngII）是肾小球疾病的关键贡献者，可能调节非肾细胞中的 TRPC6 表达。我们证明 AngII 可调节培养的足细胞中 TRPC6 的 mRNA 和蛋白水平，并且 AngII 输注可增强体内肾小球 TRPC6 的表达。在人类 FSGS（阿霉素肾病）和肾素-血管紧张素系统活性增加（Ren2 转基因大鼠）的动物模型中，肾小球 TRPC6 的表达以 AngII 依赖性方式增加。TRPC6 的表达与肾小球损伤标志物和肾小球硬化相关。我们表明，AngII 和阿霉素对 TRPC6 表达的调节需要 TRPC6 介导的 Ca2+内流以及 Ca2+依赖性蛋白磷酸酶钙调神经磷酸酶及其底物活化 T 细胞核因子（NFAT）的激活。因此，环孢素抑制钙调神经磷酸酶可降低阿霉素肾病中的 TRPC6 表达和蛋白尿，而足细胞特异性诱导表达组成型激活的 NFAT 突变体可增加 TRPC6 表达并诱导严重蛋白尿。我们的研究结果表明，AngII 对足细胞的有害影响及其在肾小球疾病中的致病作用涉及通过钙调神经磷酸酶/NFAT 正反馈信号通路增强 TRPC6 表达。
